Journal Article

CANCER BIOLOGY: Drug-resistant breast cancer cells frequently retain expression of a functional wild-type p53 protein

Jean M. Gudas, Hoang Nguyen, Tao Li, Lisa Sadzewicz, Robert Robey, Katja Wosikowksi and Kenneth H. Cowan

in Carcinogenesis

Volume 17, issue 7, pages 1417-1427
Published in print July 1996 | ISSN: 0143-3334
e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.7.1417
CANCER BIOLOGY: Drug-resistant breast cancer cells frequently retain expression of a functional wild-type p53 protein

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Abnormalities in the p53 tumor suppressor gene have been shown to affect cellular processes related to cell cycle control and gene amplification. In this study we compare the status and function of wild-type p53 in MCF-7 breast cancer cells with sublines selected for resistance to chemo-therapeutic agents having different mechanisms of action. Sublines that were resistant to melphalan, pyrazafurin, mitoxantrone, etoposide and PALA all retained expression of wild-type p53. Methotrexate-resistant MCF-7 cells were unusual heterozygotes that expressed a wild-type and dominant, in-frame p53 deletion mutant and the doxorubicin-resistant cells expressed only mutant p53. Analysis of the Gl checkpoint after treatment with ionizing radiation revealed that the pyrazafurin-, melphalan- and mitoxan-trone-resistant cells arrested strongly in Gl. The etoposide-and PALA-resistant cells had an intermediate Gl arrest phenotype and the methotrexate- and doxorubicin-resistant cells had a minimal Gl arrest phenotype. mRNA and protein analyses of downstream effector genes, including p21CIP1A/Waf1, mdm2, Gadd 45 and the retinoblastoma protein, did not entirely differentiate sublines having a strong versus intermediate Gl arrest phenotype. Neither the p53 status nor the strength of the Gl arrest could be correlated with cell survival after ionizing radiation. When drug-sensitive MCF-7 cells were treated with the same chemotherapeutic agents, p53 and p21CIPI/Waf1 levels increased between 2-and 14-fold. Together these data suggest that other cellular factors likely play a role in overcoming the inhibitory effects of ionizing radiation on p53 in drug-resistant breast cancer cells.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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